1. Field of the Invention
This invention relates to the transdermal delivery of drugs. More particularly, this invention relates to preventing contact sensitization to a skin sensitizing drug by inducing tolerance to the drug.
2. Description of the Prior Art
The transdermal route of parenteral drug delivery provides many advantages and transdermal systems for delivering a wide variety of drugs and other beneficial agents are known and described in U.S. Pat. Nos. 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454; 4,559,222 and 4,573,995, for example, all of which are incorporated herein by reference.
Unfortunately however, many drugs which appear to be ideal candidates for transdermal delivery have a tendency to sensitize human patients. This is especially true for drugs which are transdermally or transmucosally administered for sustained periods of time. The sensitizing drugs can cause undesirable skin reactions, a condition known as contact sensitivity or contact allergy. Therefore, despite the development of the transdermal drug delivery art, there remains a continuing need for an improved method of overcoming contact sensitization caused by transdermal or transmucosal delivery of a sensitizing drug.
Sensitization is a two-phase process involving distinct biological mechanisms of the human immune system. The first phase is called the induction phase. Induction occurs when the skin of individual is first exposed to the sensitizing drug. In this phase, the sensitizing drug or antigen is presented to the T-lymphocytes (T-cells) by the Langerhans cells of the epidermis, either in situ or in the draining lymph node. As a consequence, T-cells which recognize the antigen, proliferate and to some extent differentiate. Generally, no visible skin reaction is noted during the induction phase. Following induction, the individual's lymphocytes are specifically sensitized to the drug.
The second phase of sensitization is called elicitation. Elicitation occurs when the individual is subsequently (i.e., after induction) exposed to the same sensitizing drug. Elicitation causes a skin reaction to occur. The skin reaction occurring during elicitation is known as contact dermatitis. During elicitation, the antigen is once again presented mainly on the Langerhans cells. The T-cells, which have proliferated upon prior exposure to the drug (i.e., during the induction phase), now come to the treated site and initiate toxic events which result in local inflammation (i.e., contact dermatitis).
Irritation on the other hand is a completely different phenomenon from contact (i.e., skin) sensitization. Skin irritation can be caused by a variety of factors including, but not limited to, physical factors (e.g., chafing or occluding the skin in an air-tight manner), exposure to certain chemicals, exposure to pH outside the normal pH range of the skin or mucosa and bacterial overgrowth. Generally, irritation is the result of damage to cells in the skin or mucosa caused by their response to a toxic (i.e., irritating) agent. Sensitization on the other hand, is the result of a response by the immune system to an agent (i.e., an antigen) which is not necessarily irritating.
Corticosteroids are known anti-inflammatory agents and are commonly used to alleviate the skin reactions occurring during the elicitation phase of sensitization and to alleviate the after-effects of skin irritation. For example, corticosteroids have been administered with another drug, such as an antibiotic, in order to treat existing inflammation at the site of a skin infection. See Fawzi U.S. Pat. No. 4,343,798.
Investigators have found that corticosteroids are effective in reducing and/or preventing skin irritation in guinea pigs and rabbits caused by skin occlusion. For example, in Japanese Kokai No. 60-23,312, Nitto Electric Ind. Co. (1985), corticosteroids are delivered from a transdermal skin patch. Nitto teaches that when the patch is applied to the skin in an air-tight manner, the barrier properties of the skin are reduced thereby making it easier for the drug to permeate through the skin. Nitto further teaches that (i) these air-tight skin patches do not allow moisture from the skin to evaporate, and (ii) the retained moisture eventually causes inflammation. Nitto delivers a small amount of an anti-inflammatory corticosteroid, together with the drug, in order to reduce the inflammation caused by the moisture retained in the skin.
Immune tolerance is a different phenomenon from both sensitization and irritation. Immune tolerance is the state of prolonged unresponsiveness to a specific antigen. Tolerance has been induced experimentally in several animal species by administration of the antigen to fetal or neonatal animals. Tolerance can also be induced for certain antigens by injecting the antigen in a non-immunizing form. This has been accomplished for example with gamma globulin cleared of aggregates by extensive high speed centrification. In addition, tolerance to contact sensitization has been induced in adult animals (i) by pretreatment of the skin site to which the sensitizing antigen is applied with compounds which act to suppress the animal's immune system (See The Journal of Immunology, Vol. 136, No. 3, Rheins & Nordlund, pp. 867-876, (1986)) or (ii) by UV irradiation (See Photodermatology, Vol. 5, Cruz et al, pp. 126-132 (1988)). Immune tolerance to contact sensitizers was induced in mice by delivering several doses of UV irradiation (Cruz et al) or by application of arachidonic acid to the local site for several days prior to antigen application (see Rheins & Nordlund). In the later study, a systemic effect on the entire immune system of the mice, rather than any local effect, was not ruled out. However, other investigators have found that while immune tolerance could be induced in certain strains of mice by UV irradiation, in other strains of mice tolerance could not be so induced. See The Effect of Ultraviolet Radiation on the Immune System, chapter 5, Bergstresser et al, pp. 73-86 (1983). Clearly then it is difficult to predict whether or not immune tolerance can be induced topically in different animal strains. Those skilled in the art of skin sensitization can readily appreciate the difficulty in predicting the occurrence of immune tolerance by extrapolating from one animal species to another. Other investigators have found that pretreating human skin with betamethasone valerate can prevent induction of sensitization to a normally sensitizing compound (e.g., dinitrochlorobenzene). See Arch. Dermatol., vol. 112, Burrows et al, pp. 175-8 (1976). However, these same investigators failed to induce tolerance to dinitrochlorobenzene.
In general, once the skin has become sensitized, skin reactions occurring after re-exposure to the sensitizing agent are difficult if not impossible to prevent. For that reason, this invention is directed towards preventing sensitization from occurring, rather than treating problems of pain and discomfort occurring during the elicitation phase (i.e, after sensitization has already been induced).